Alzheimer's disease (AD) is a major neurodegenerative disease for which there is currently no effective prevention or treatment. Amyloid-beta protein (Abeta) accumulation and accompanying inflammation appear to play key roles in initiating the pathogenesis of the neuronal degeneration that underlies the symptoms of AD. Reducing Abeta levels and/or its associated inflammation may delay or prevent the onset of the disease. Recent reports by several research groups, including ours, have shown that Abeta vaccination lowers cerebral Abeta in transgenic mice and can result in improved behavior. We hypothesize that chronic mucosal Abeta immunization with Abeta plus mucosal adjuvants induces a specific and sustained anti-Abeta response that, via clearance through Fc(gamma)-receptors and/or complement receptors, strongly lowers Abeta burden, resulting in reduced inflammation and neuronal degeneration. The central goal of this proposal is to advance this hypothesis in preparation for application to humans. Our Specific Aims are: 1) to systematically determine the optimal immunization protocol for an effective mucosal (oral or nasal), transcutaneous, or combined (e.g., parenteral, then nasal) Abeta vaccine in wildtype (non-transgenic) mice, using various adjuvants, Abeta peptides and dosing schedules; 2) to determine the effectiveness of our optimized Abeta immunization protocol (from Aim 1) in each of 3 transgenic mouse models (APP, PS 1 and PSAPP) as well as for reduction of AA amyloid in a chemically- or genetically-induced mouse model of systemic AA amyloidosis; 3) to study the mechanism of Abeta immunization in vivo by assessing the role of complement, complement receptors (CR1 and CR3) and Fc(gamma)-receptors in Abeta reduction following immunization by immunizing (with our optimized protocol from Aim 1) APP transgenic mice crossbred with mice genetically deficient for either Clq, C3 or the Fc(gamma)-receptors RI and RIII. Our plan utilizes multiple routes of immunization, a diverse range of adjuvants and multiple mouse models, including 3 lines of Abeta-overproducing transgenic mice (APP, PS 1, PSAPP), mice with systemic AA amyloidosis, and 3 knockout mice lines (Clq-/-, C3-/- and Fc(gamma)R-/-). Multiple outcome measures will determine the effects of Abeta immunization on humoral and cell-mediated responses, as well as on cerebral Abeta burden and its associated inflammation. We believe our validated nasal mucosal immunization approach represents a unique and efficacious route for Abeta vaccination that could be convenient and well-tolerated, and thus provide a highly attractive method for prevention and treatment of AD in aged humans.